US7232835B2 - 3,6-Disubstituted azabicyclo derivatives as muscarinic receptor antagonists - Google Patents

3,6-Disubstituted azabicyclo derivatives as muscarinic receptor antagonists Download PDF

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US7232835B2
US7232835B2 US10/537,851 US53785102A US7232835B2 US 7232835 B2 US7232835 B2 US 7232835B2 US 53785102 A US53785102 A US 53785102A US 7232835 B2 US7232835 B2 US 7232835B2
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azabicyclo
hexyl
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cyclohexyl
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US20060217432A1 (en
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Anita Mehta
Arundutt Viswanatham Silamkoti
Bruhaspathy Miriyala
Sudershan Kumar Arora
Boju Srinivasulu
Bireshwar Mukherjee
Jang Bahadur Gupta
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Ranbaxy Laboratories Ltd
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Definitions

  • This invention relates to the derivatives of 3,6-disubstituted azabicyclo compounds.
  • the compounds of this invention can function as muscarinic receptor antagonists, and can be used for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems mediated through muscarinic receptors.
  • the invention also relates to pharmaceutical compositions containing the compounds of the present invention and the methods of treating the diseases mediated through muscarinic receptors.
  • Muscarinic receptors as members of the G Protein Coupled Receptors are composed of a family of 5 receptor sub-types (M 1 , M 2 , M 3 , M 4 and M 5 ) and are activated by the neurotransmitter acetylcholine. These receptors are widely distributed on multiple organs and tissues and are critical to the maintenance of central and peripheral cholinergic neurotransmission. The regional distribution of these receptor sub-types in the brain and other organs has been documented.
  • the M 1 subtype is located primarily in neuronal tissues such as cereberal cortex and autonomic ganglia
  • the M 2 subtype is present mainly in the heart where it mediates cholinergically induced bradycardia
  • the M 3 subtype is located predominantly on smooth muscle and salivary glands ( Nature , 1986; 323: 411; Science, 1987; 237: 527).
  • Muscarinic agonists such as muscarine and pilocarpine and antagonists such as atropine have been known for over a century, but little progress has been made in the discovery of receptor subtype-selective compounds making it difficult to assign specific functions to the individual receptors.
  • classical muscarinic antagonists such as atropine are potent bronchodilators, their clinical utility is limited due to high incidence of both peripheral and central adverse effects such as tachycardia, blurred vision, dryness of mouth, constipation, dementia, etc.
  • the present invention provides derivatives of 3,6-disubstituted azabicyclo compounds as muscarinic receptor antagonists and are useful for the safe and effective therapeutic or prophylactic agents for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems, and process for the synthesis of the novel compounds.
  • the invention also provides pharmaceutical compositions containing the compounds, and which may also contain acceptable carriers, excipients or diluents which are useful for the treatment of various diseases of the respiratory, urinary and gastrointestinal systems.
  • the present invention also includes within its scope prodrugs of the compounds.
  • prodrugs are functionalized derivatives of these compounds which readily get converted in vivo into the defined compounds.
  • Conventional procedures for the selection and preparation of suitable prodrugs are known to the artisan of ordinary skill in the art.
  • the invention also includes the enantiomers, diastereomers, N-oxides, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters and metabolites of these compounds having the same type of activity.
  • the invention further includes pharmaceutical compositions comprising the compounds of the present invention, their prodrugs, metabolites, enantiomers, diastereomers, N-oxides, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates or esters, in combination with a pharmaceutically acceptably carrier and optionally included excipients.
  • R 3 , R 4 and s are as defined for Formula V.
  • the compounds of the present invention may be prepared by the reaction sequence as shown in Scheme I
  • the preparation comprises condensing a compound of Formula VII with the compound of Formula VIII wherein
  • This compound was synthesized following the procedure of Example 10 by using 1,3-dibromopropane in step a instead of 1,4-dibromobutane.
  • This compound was synthesized following the procedure of Example 10 by reacting 2-propyloxy-2,2-diphenyl acetic acid as obtained in Example 5 and 6-[N- ⁇ -bromopropyl, N-tert-butyloxycarbonyl, N-3-benzyl-3-azabicyclo[3.1.0]hexane].
  • This compound was synthesized following the procedure of Example 10 by reacting 2-propyloxy-2,2-diphenyl acetic acid as obtained in Example 5 and 6-[N- ⁇ -bromobutyl, N-tert-butyloxycarbonyl, N-3-benzyl-3-azabicyclo[3.1.0]hexane].
  • This compound was synthesized following the procedure as described in Example 10 by reacting 2-(2-propenyloxy)-2,2-diphenyl acetic acid as obtained in Example 3 and 6-[N- ⁇ -bromobutyl, N-tert-butyloxycarbonyl, N-3-benzyl-3-azabicyclo [3.1.0]hexane].
  • Example 17 The title compound was synthesized following the procedure described in Example 17 using 2-propenyloxy-2,2-diphenyl acetic acid as obtained in Example 3 instead of 2-propyloxy-2,2-diphenyl acetic acid, and 6-N-chloromethylcarbonyl-3-N-benzyl-3-azabicyclo[3.1.0]hexane.
  • Example 17 The title compound was synthesized following the procedure as described in Example 17 by reacting 2-propenyloxy-2,2-diphenyl acetic acid as obtained in Example 3, with 6-N-chloromethylcarbonyl-3-N-benzyl-3-azabicyclo[3.1.0]hexane.
  • Example 17 The title compound was synthesized following the procedure of Example 17 by using 2-propyloxy-2,2-diphenyl acetic acid as obtained in Example 5.
  • step b was prepared following the procedure as described in step c of Example 1 using 2-hydroxy-2-cyclohexyl phenyl acetic acid instead of 2-hydroxy-2,2-diphenyl acetic acid.
  • Example 22 The compound obtained in Example 22 was debenzylated and then N-alkylated as given below:
  • This compound was synthesized following the procedure as in Example 23 but using 4-bromobenzyl bromide instead of 3,5-difluoro benzyl bromide.
  • step a of Example 23 The compound obtained in step a of Example 23 (300 mg; 1 mmol) was dissolved in acetonitrile (20 ml) and potassium carbonate (1.5 mmol), potassium iodide (catalytical amount) were added to it at room temperature. It was followed by the addition of 2-phenyl ethyl bromide to the reaction mixture and was stirred at reflux for 8 hrs. The reaction mixture was filtered and the filtrate was taken in ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulphate. It was concentrated under reduced pressure and purified over silica gel (100–200 mesh) using ethyl acetate/hexane mixture.
  • This compound was synthesized following the procedure as described in step b of Example 23 but using n-propyl bromide instead of 3,5-difluoro benzyl bromide.
  • This compound was synthesized following the procedure as in Example 23 using propargyl bromide instead of 3,5-difluoro benzyl bromide.
  • This compound was synthesized following the procedure as described in Example 23 using allyl bromide instead of 3,5-difluoro benzyl bromide.
  • This compound was synthesized following the procedure as in Example 23 using propyl bromide instead of 3,5-difluoro benzyl bromide.
  • This compound was synthesized following the procedure as described in Example 23 but using cyclopropyl bromide instead of 3,5-difluoro benzyl bromide.
  • This compound was synthesized following the procedure as described in Example 23 using n-butyl bromide instead of 3,5-difluoro benzyl bromide.
  • This compound was synthesized following the procedure as in Example 23 using isopropenyl bromide instead of 3,5-difluoro benzyl bromide.
  • This compound was synthesized following the procedure as described in Example 46, using 4-methoxy-acetylphenylisocyanate instead of phenyl thiocyanate.
  • This compound was synthesized following the procedure as described in Example 46 using 4-methylphenyl-1-sulphonamide cyanate instead of phenyl thiocyanate.
  • This compound was synthesized following the procedure as in Example 50 using 2-(4-methoxyphenyl)-2-cyclohexyl-2-hydroxy acetic acid instead of 2-(4-methylphenyl)-2-cyclohexyl-2-hydroxy acetic acid.
  • This compound was synthesized following the procedure as described in Example 50 using 2-(4-phenoxyphenyl)-2-cyclohexyl-2-hydroxy acetic acid instead of 2-(4-methylphenyl)-2-cyclohexyl-2-hydroxy acetic acid.
  • This compound was synthesized following the procedure as described in Example 50 using 2-(4-fluorophenyl)-2-cyclohexyl-2-hydroxy acetic acid instead of 2-(4-methylphenyl)-2-cyclohexyl-2-hydroxy acetic acid.
  • This compound was synthesized following the procedure as described in Example 50 using 2-(3,4-methylenedioxyphenyl)-2-cyclohexyl-2-hydroxy acetic acid instead of 2-(4-methylphenyl)-2-cyclohexyl-2-hydroxy acetic acid.
  • This compound was synthesized following the procedure as described in Example 50 using 2-(4-tertbutylphenyl)-2-cyclohexyl-2-hydroxy acetic acid instead of 2-(4-methylphenyl)-2-cyclohexyl-2-hydroxy acetic acid.
  • Example 50 The compound from Example 50 was debenzylated following the procedure as given in Example 23 to afford 6-N-(3-azabicyclo[3.1.0]cyclohexyl)-2-hydroxy-2-cyclohexyl-2-(4-methylphenyl)acetamide.
  • This compound was synthesized following the procedure as described in Example 56 using 6-N-(3-azabicyclo[3.1.0]hexyl)-2-hydroxy-2-cyclohexyl-2-(4-fluorophenyl)acetamide instead of 6-N-(3-azabicyclo[3.1.0]hexyl)-2-hydroxy-2-cyclohexyl-2-(4-methylphenyl)acetamide.
  • This compound was synthesized following the procedure as described in Example 23, using 6-N-(3-azabicyclo[3.1.0]hexyl)-2-methoxy-2-cyclohexyl-2-phenyl acetamide instead of 6-N-(3-azabicyclo[3.1.0]hexyl)-2-hydroxy-2-cyclohexyl-2-phenyl acetamide in step a, and ethyl bromide instead of 3,5-difluoro benzyl bromide in step b of Example 23.
  • This compound was synthesized following the procedure as described in Example 3, using ethyl-2-hydroxy-2-cyclohexyl phenyl acetate instead of ethyl-2-hydroxy-2,2-diphenyl acetate in step (i) a, and ethyl-2-allyloxy-2-cyclohexyl-2-phenyl acetate instead of ethyl-2-allyloxy-2,2-diphenyl acetate in step (ii) a of Example 3.
  • This compound was synthesized following the procedure as described in Example 23 using 6-N-(3-azabicyclo[3.1.0]hexyl)-2-methoxy-2-cyclohexyl-2-phenyl acetamide instead of 6-N-(3-azabicyclo[3.1.0]hexyl)-2-hydroxy-2-cyclohexyl-2-phenyl acetamide in step a, and 4-methyl-3-pentenyl bromide instead of 3,5-difluoro benzyl bromide in step b of Example 23.
  • This compound was synthesized following the procedure as described in Example 23 using 6-N-(3-azabicyclo[3.1.0]hexyl)-2-methoxy-2-cyclohexyl-2-phenyl acetamide instead of 6-N-(3-azabicyclo[3.1.0]hexyl)-2-hydroxy-2-cyclohexyl-2-phenyl acetamide in step a, and 2,4-difluorobenzyl bromide instead of 3,5-difluoro benzyl bromide in step b of Example 23.
  • the compound was synthesized starting from Compound No. 64, which was debenzylated following the method as described in step a of Example 23, and then N-alkylated as given in Example 41.
  • the compound was synthesized starting from Compound No. 64, which was debenzylated following the method as described in step a of Example 23, and then N-alkylated as given in Example 29.
  • Example 28 The compound was synthesized starting from Compound No. 64 which was debenzylated following the method as described in step a of Example 23, and then N-alkylated as given in Example 28.
  • the compound was synthesized starting from Compound No. 64, which was debenzylated following the method as described in step a of Example 23, and then N-alkylated as given in Example 30.
  • the compound was synthesized starting from Compound No. 64, which was debenzylated following the method as described in step a of Example 23, and then N-alkylated as given in Example 31.
  • Step b The title compound was synthesized following the procedure as described in step c of Example 85 using 2-hydroxy-2-cycloheptyl-2-phenyl acetic acid instead of 2-hydroxy-2,2-diphenyl acetic acid.
  • the compound was synthesized starting from Compound No. 72, which was debenzylated following the method as described in step a of Example 23, and then N-alkylated as given in example 41.
  • Step a Preparation of 2-amino-(1 ⁇ ,5 ⁇ ,6 ⁇ )-6-N-(3-azabicyclo[3.1.0]hexyl-3-benzyl) propionamide: 2-(Boc-amino)propionic acid was condensed with (1 ⁇ ,5 ⁇ ,6 ⁇ )-6-amino-3-azabicyclo[3,1,0]hexane, following the procedure as described in step c of Example 85. The N-Boc compound thus obtained was deprotected with 10% trifluoro acetic acid in dichloromethane to afford the free amino compound.
  • This compound was synthesized following the procedure as described in Example 74 using 2-(Boc-amino)acetic acid in step a instead of 2-(Boc-amino)propionic acid.
  • This compound was synthesized following the procedure as described in Example 74, using 3-(Boc-amino)propionic acid in step a instead of 2-(Boc-amino)propionic acid.
  • This compound was synthesized following the procedure as described in Example 75, but using 3-hydroxy-3-phenyl-3-cyclohexyl-propionic acid in step b instead of 2-hydroxy-2-cyclohexyl-2-phenyl acetic acid.
  • This compound was synthesized following the procedure as described in Example 74, but using 3-hydroxy-3-phenyl-3-cyclohexyl-propionic acid in step b instead of 2-hydroxy-2-cyclohexyl-2-phenyl acetic acid.
  • step b To a solution of the compound of step b (0.3 g, 0.74 mmol) in methanol (10.0 ml), 10% Pd—C (0.3 g) was added and the reaction mixture was stirred at room temperature for 2 hours under an atmosphere of H 2 . The reaction mixture was filtered through a bed of hyflo and the bed was washed with methanol (10.0 ml). The filtrate was concentrated under vacuum to give the title compound in 77% (0.18 g, 0.57 mmol) yield.
  • This compound is prepared in 90% yield following a procedure directly analogous to that of step c of Example 85.
  • This compound is prepared in 90% yield following a procedure directly analogous to that of step c of Example 85.
  • This compound is prepared in 90% yield following a procedure directly analogous to that of step c of Example 85, using the product of step a here instead of that of Example 85.
  • This compound is prepared in 96% of yield following a procedure directly analogous to that of step c, of Example 85.
  • step a To a solution of compound of step a (0.304 g, 1.3 mmol) and the compound of step b (0.23 g, 0.87 mmol) in xylene (15 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.2 g, 1.3 mmol) and the reaction mixture was refluxed for 3 hours. The reaction mixture was directly adsorbed over silicagel and purified by column chromatography using 60% ethylacetate in hexane to get the title compound in 95% yield.
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • This compound was synthesized in direct analogy to the procedure of Example 93 by using 2-chloropropionyl chloride in step b, Example 93 instead of chloroacetyl chloride.
  • Step c Preparation of (1 ⁇ ,5 ⁇ ,6 ⁇ )-4-[6-N-(3-azabicyclo-[3.1.0]hexyl-3-benzyl)]-N-(tert-butyloxycarbonyl)butyl-1-[2-hydroxy-2,2-bis-(4-fluorophenyl)]acetate
  • test compounds for M 2 and M 3 muscarinic receptor subtypes were determined by [ 3 H]-N-methylscopolamine binding studies using rat heart and submandibular gland respectively as described by Moriya et al., ( Life Sci, 1999, 64(25):2351–2358) with minor modifications.
  • Membrane preparation Submandibular glands and heart were isolated and placed in ice cold homogenising buffer (HEPES 20 mM, 10 mM EDTA, pH 7.4) immediately after sacrifice. The tissues were homogenised in 10 volumes of homogenising buffer and the homogenate was filtered through two layers of wet gauze and filtrate was centrifuged at 500 g for 10 min. The supernatant was subsequently centrifuged at 40,000 g for 20 min. The pellet thus obtained was resuspended in same volume of assay buffer (HEPES 20 mM, EDTA 5 mM, pH 7.4) and were stored at ⁇ 70° C. until the time of assay.
  • HEPES 20 mM, 10 mM EDTA, pH 7.4 ice cold homogenising buffer
  • Ligand binding assay The compounds were dissolved and diluted in DMSO. The membrane homogenates (150–250 ⁇ g protein) were incubated in 250 ⁇ l of assay buffer (HEPES 20 mM, pH 7.4) at 24–25° C. for 3 h. Non-specific binding was determined in the presence of 1 ⁇ M atropine. The incubation was terminated by vaccum filtration over GF/B fiber filters (Wallac). The filters were then washed with ice cold 50 mM Tris HCl buffer (pH 7.4). The filter mats were dried and bound radioactivity retained on filters was counted. The IC 50 & Kd were estimated by using the non-linear curve fitting program using G Pad Prism software.
  • Ki inhibition constant
  • the bladder was cut into longitudinal strips (3 mm wide and 5–6 mm long) and mounted in 10 ml organ baths at 30° C., with one end connected to the base of the tissue holder and the other end connected to a polygraph through a force displacement transducer. Each tissue was maintained at a constant basal tension of 2 g and allowed to equilibrate for 1 hour during which the PSS was changed every 15 min. At the end of equilibration period, the stabilization of the tissue contractile response was assessed with 1 ⁇ Mol/L of Carbachol consecutively for 2–3 times. Subsequently, a cumulative concentration response curve to carbachol (10 ⁇ 9 mol/L to 3 ⁇ 10 ⁇ 5 mol/L) was obtained. After several washes, once the baseline was achieved, cumulative concentration response curve was obtained in the presence of NCE (NCE added 20 min. prior to the second CRC).

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US20070287732A1 (en) * 2003-04-10 2007-12-13 Ranbaxy Laboratories Limited Substituted Azabicyclo Hexane Derivatives as Muscarinic Receptor Antagonists
US20080319043A1 (en) * 2005-05-03 2008-12-25 Mohammad Salman 3,6-Disubstituted Azabicyclo (3.1.0) Hexane Derivatives as Muscarinic Receptor Antagonists
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US7544708B2 (en) 2002-07-08 2009-06-09 Ranbaxy Laboratories Limited Azabicyclo derivatives as muscarinic receptor antagonists
US20070287732A1 (en) * 2003-04-10 2007-12-13 Ranbaxy Laboratories Limited Substituted Azabicyclo Hexane Derivatives as Muscarinic Receptor Antagonists
US7592359B2 (en) * 2003-04-10 2009-09-22 Ranbaxy Laboratories Limited Substituted azabicyclo hexane derivatives as muscarinic receptor antagonists
US20060287380A1 (en) * 2003-04-11 2006-12-21 Mohammad Salman Azabicyclo Derivatives as Muscarinic Receptor Antagonists
US7446123B2 (en) 2003-04-11 2008-11-04 Ranbaxy Laboratories Limited Azabicyclo derivatives as muscarinic receptor antagonists
US20100035954A1 (en) * 2004-12-15 2010-02-11 Mohammad Salman Acid addition salts of muscarinic receptor antagonists
US20080319043A1 (en) * 2005-05-03 2008-12-25 Mohammad Salman 3,6-Disubstituted Azabicyclo (3.1.0) Hexane Derivatives as Muscarinic Receptor Antagonists
US11274082B2 (en) 2019-05-31 2022-03-15 Ikena Oncology, Inc. Tead inhibitors and uses thereof
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EP1572648B1 (fr) 2008-07-09
WO2004052857A1 (fr) 2004-06-24
JP2006518707A (ja) 2006-08-17
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HK1085724A1 (en) 2006-09-01
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